The present application for continuing K24 support is a logical extension of productive mentorship and research progress during the prior cycle of funding, during which three K08 mentees achieved fundable R01 priority scores;the Cleveland Clinic Lerner College of Medicine (CCLCM) research program was integrated into the PI's mentorship activities;laboratory post-docs achieved independent funding and/or faculty positions;and several external mentees competed successfully for funding. We now seek support to expand mentorship interactions with the CCLCM through membership on the Research Education Committee (REC), which sets research policy and develops tools to assist research mentors with their mission to graduate clinician-scientists from the CCLCM. Integral to this activity is a structured evaluation process during which the PI will meet regularly with Dr. Christine Taylor, Director of Faculty Development for the Cleveland Clinic, and discuss student feedback, which will be used to develop enhance research mentoring at the CCLCM. The present application also benefits from establishment of the NIH/NCRR-funded Case Western Reserve University School of Medicine (CWRU-SOM)/Cleveland Clinic Clinical and Translational Science Collaborative (CTSC), which includes a clinician-scientist KL2 mentored post-doctoral program. The applicant will join the Multidisciplinary Advisory Committee (MAC) for the CTSC, participating in selection and mentorship of KL2 clinician-scientist awardees. Together, these activities represent a significant new direction for the applicant within the Cleveland Clinic's research education program. The research proposal also takes advantage of the PI's development of a novel flow-enhanced in-vitro blood-brain barrier (BBB) model, which will be used to examine how chemokine receptors are modulated by leukocyte-endothelial interactions under flow. These experiments incorporate chemokines and a brain microvascular endothelial cell monolayer, and assays are conducted in a modified chemotaxis chamber developed specifically for this research. Specific research aims are: Aim 1: To define how chemokine CXCL12 signals selectively to monocytes to promote transmigration of lymphocytes. Aim 2: To establish how luminal 'arrest'chemokines modulate chemokine receptor expression on transmigrated cells. Aim 3: To determine how abluminal 'transmigration'chemokines regulate chemokine receptor expression on transmigrated cells. Students and post-docs participate in both the basic and clinical/translational elements of research using this novel system and use their own data to address which chemokine receptors represent logical targets for therapeutic intervention in neurological disease. PUBLIC HEALTH RELEVANCE: The present application for continuing K24 support is a logical extension of productive mentorship and research progress during the prior cycle of funding, during which three mentored junior clinician-scientists prepared successful grant applications;the applicant participated fully in training medical students to perform research at an innovative medical school (the Cleveland Clinic Lerner College of Medicine (CCLCM);and the applicant mentored students from the high school level through post-doctoral fellowship with a high degree of success and productivity. He now seeks support to expand mentorship interactions with the CCLCM through membership on the Research Education Committee (REC), which reviews thesis project proposals, sets research policy and priorities for the CCLCM and develops tools to assist research mentors with their mission to graduate clinician- scientists from the CCLCM. He will incorporate a structured self-assessment plan, which will be used to enhance mentorship at the CCLCM. The applicant also proposes to participate in a new citywide clinical- translational research collaboration (newly funded by the National Institutes of Health) and will participate in choosing clinician scientists for research mentorship support, as well as in the mentoring process itself. Therefore, the applicant will integrate his extensive experience with mentorship into innovative and vigorous local/institutional programs. The research proposal focuses on a complex yet crucial question regarding the treatment of brain inflammation: how do we identify the safest and most important molecular targets, when we wish to block inflammatory white blood cells from migrating into the brain? The applicant has developed a new tissue-culture model which promises to accelerate research progress. Furthermore, research trainees working with this model will obtain experience doing bench work, and also in the design and interpretation of clinical-research experiments. Students and post-docs can participate in both the basic-science and clinical/translational elements of research using this novel system. Ultimately, they can use their own data to address which molecules represent logical targets for therapeutic blockade to ameliorate inflammatory neurological diseases.